Developmental differences in locomotor responsiveness to amphetamine in rats

dc.contributor.author

Mathews, Iva

dc.date.accessioned

2011-10-14T15:30:52Z

dc.date.available

2011-10-14T15:30:52Z

dc.date.issued

2011-10-14

dc.identifier.uri

http://hdl.handle.net/10464/3424

dc.description.abstract

The developmental remodelling of motivational systems that underlie drug
dependence and addiction may account for the greater frequency and severity of drug
abuse in adolescence compared to adulthood. Recent advances in animal models have
begun to identify the morphological and the molecular factors that are being remodelled,
but little is known about the culmination of these factors in altered sensitivity to
psycho stimulant drugs, like amphetamine, in adolescence. Amphetamine induces potent
locomotor activating effects in rodents through increased dopamine release in the
mesocorticolimbic dopamine system, which makes locomotor activity a useful
behavioural marker of age differences in amphetamine sensitivity. The aim of the thesis
was to investigate the neural basis for age differences in amphetamine sensitivity with a
focus on the nucleus accumbens and the medial prefrontal cortex, which initiate and
regulate amphetamine-induced locomotor activity, respectively.
In study 1, I found pre- and post- pubertal adolescent rats to be less active (i.e.,
hypoactive) than adults to a first injection of 0.5, but not of 1.5, mg/kg of intraperitonealy
(i.p.) administered amphetamine. Although initially hypoactive, only adolescent rats
exhibited an increase in activity to a second injection of amphetamine given 24 h later,
indicating that adolescents may be more sensitive to the rapid changes in amphetamineinduced plasticity than adults. Given that the locomotor activating effects of
amphetamine are initiated in the nucleus accumbens, age differences in response to direct
injections of amphetamine into this brain region were investigated in study 2. In contrast
to i.p. injections, adolescents were more active than adults when amphetamine was given directly into the nucleus accumbens, indicating that hypo activity may be attributed to the
development of regulatory regions outside of the accumbens.
The medial prefrontal cortex (mPFC) is a key regulator of the locomotor
activating effects of amphetamine that undergoes extensive remodelling in adolescence.
In study 3, I found that an i.p. injection of 1.5, and not of 0.5, mg/kg of amphetamine
resulted in a high expression of c-fos, a marker of neural activation, in the pre limbic
mPFC only in pre-pubertal adolescent rats. This finding suggests that the ability of
adolescent rats to overcome hypo activity at the 1.5 mg/kg dose may involve greater
activation of the prelimbic mPFC compared to adulthood. In support of this hypothesis, I
found that pharmacological inhibition of prelimbic D 1 dopamine receptors disrupted the
locomotor activating effects of the 1.5 mg/kg dose of amphetamine to a greater extent in
adolescent than in adult rats. In addition, the stimulation of prelimbic D 1 dopamine
receptors potentiated locomotor activity at the 0.5 mg/kg dose of amphetamine only in
adolescent rats, indicating that the prelimbic D1 dopamine receptors are involved in
overcoming locomotor hypoactivity during adolescence.
Given my finding that the locomotor activating effects of amphetamine rely on
slightly different mechanisms in adolescence than in adulthood, study 4 was designed to
determine whether the lasting consequences of drug use would also differ with age. A
short period of pre-treatment with 0.5 mg/kg of amphetamine in adolescence, but not in
adulthood, resulted in heightened sensitivity to an injection of amphetamine given 30
days after the start of the procedure, when adolescent rats had reached adulthood. The
finding of an age-specific increase in amphetamine sensitivity is consistent with evidence
for increased risk for addiction when drug use is initiated in adolescence compared to adulthood in people (Merline et aI., 2002), and with the hypothesis that adolescence is a
sensitive period of development.

en_US

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eng

en_US

dc.publisher

Brock University

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dc.subject

Amphetamines -- Physiological effect.

en_US

dc.subject

Animal behavior

en_US

dc.subject

Drug abuse

en_US

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Youth -- Drug use

en_US

dc.title

Developmental differences in locomotor responsiveness to amphetamine in rats